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Hydrolase PDB id
1bc2
Jmol
Contents
Protein chains
216 a.a. *
Ligands
SO4 ×2
Metals
_ZN ×4
Waters ×400
* Residue conservation analysis
PDB id:
1bc2
Name: Hydrolase
Title: Zn-dependent metallo-beta-lactamase from bacillus cereus
Structure: Metallo-beta-lactamase ii. Chain: a, b. Other_details: starting material has several ragged n- termini
Source: Bacillus cereus. Organism_taxid: 1396. Strain: 569/h/9
Resolution:
1.90Å     R-factor:   0.208     R-free:   0.279
Authors: S.M.Fabiane,B.J.Sutton
Key ref:
S.M.Fabiane et al. (1998). Crystal structure of the zinc-dependent beta-lactamase from Bacillus cereus at 1.9 A resolution: binuclear active site with features of a mononuclear enzyme. Biochemistry, 37, 12404-12411. PubMed id: 9730812 DOI: 10.1021/bi980506i
Date:
11-Apr-97     Release date:   14-Oct-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P04190  (BLA2_BACCE) -  Beta-lactamase 2
Seq:
Struc: 		257 a.a.
216 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.5.2.6  - Beta-lactamase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Penicillin Biosynthesis and Metabolism
      Reaction: A beta-lactam + H2O = a substituted beta-amino acid
      Cofactor: Zinc
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     response to antibiotic   2 terms 
  Biochemical function     hydrolase activity     4 terms  

 

 
DOI no: 10.1021/bi980506i Biochemistry 37:12404-12411 (1998)
PubMed id: 9730812  
 
 
Crystal structure of the zinc-dependent beta-lactamase from Bacillus cereus at 1.9 A resolution: binuclear active site with features of a mononuclear enzyme.
S.M.Fabiane, M.K.Sohi, T.Wan, D.J.Payne, J.H.Bateson, T.Mitchell, B.J.Sutton.
 
  ABSTRACT  
 
The structure of the zinc-dependent beta-lactamase II from Bacillus cereus has been determined at 1.9 A resolution in a crystal form with two molecules in the asymmetric unit and 400 waters (space group P3121; Rcryst = 20.8%). The active site contains two zinc ions: Zn1 is tightly coordinated by His86, His88, and His149, while Zn2 is loosely coordinated by Asp90, Cys168, and His210. A water molecule (W1) lies between the two zinc ions but is significantly closer to Zn1 and at a distance of only 1.9 A is effectively a hydroxide moiety and a potential, preactivated nucleophile. In fact, Asp90 bridges W1 to Zn2, and its location is thus distinct from that of the bridging water molecules in the binuclear zinc peptidases or other binuclear zinc hydrolases. Modeling of penicillin, cephalosporin, and carbapenem binding shows that all are readily accommodated within the shallow active site cleft of the enzyme, and the Zn1-bound hydroxide is ideally located for nucleophilic attack at the beta-lactam carbonyl. This enzyme also functions with only one zinc ion present. The Zn1-Zn2 distances differ in the two independent molecules in the crystal (3.9 and 4.4 A), yet the Zn1-W1 distances are both 1.9 A, arguing against involvement of Zn2 in W1 activation. The role of Zn2 is unclear, but the B. cereus enzyme may be an evolutionary intermediate between the mono- and bizinc metallo-beta-lactamases. The broad specificity of this enzyme, together with the increasing prevalence of zinc-dependent metallo-beta-lactamases, poses a real clinical threat, and this structure provides a basis for understanding its mechanism and designing inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21568871 L.Sun, L.Zhang, H.Zhang, and Z.G.He (2011).
Characterization of a Bifunctional β-Lactamase/Ribonuclease and Its Interaction with a Chaperone-Like Protein in the Pathogen Mycobacterium tuberculosis H37Rv.
  Biochemistry (Mosc), 76, 350-358.  
20575118 A.Tamilselvi, and G.Mugesh (2010).
Hydrolysis of organophosphate esters: phosphotriesterase activity of metallo-beta-lactamase and its functional mimics.
  Chemistry, 16, 8878-8886.  
20305272 Y.Yamaguchi, N.Takashio, J.Wachino, Y.Yamagata, Y.Arakawa, K.Matsuda, and H.Kurosaki (2010).
Structure of metallo-beta-lactamase IND-7 from a Chryseobacterium indologenes clinical isolate at 1.65-A resolution.
  J Biochem, 147, 905-915.
PDB code: 3l6n
18449576 A.Badarau, and M.I.Page (2008).
Loss of enzyme activity during turnover of the Bacillus cereus beta-lactamase catalysed hydrolysis of beta-lactams due to loss of zinc ion.
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18648861 A.Tamilselvi, and G.Mugesh (2008).
Zinc and antibiotic resistance: metallo-beta-lactamases and their synthetic analogues.
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18652482 L.A.Abriata, L.J.González, L.I.Llarrull, P.E.Tomatis, W.K.Myers, A.L.Costello, D.L.Tierney, and A.J.Vila (2008).
Engineered mononuclear variants in Bacillus cereus metallo-beta-lactamase BcII are inactive.
  Biochemistry, 47, 8590-8599.  
18551183 M.I.Page, and A.Badarau (2008).
The mechanisms of catalysis by metallo beta-lactamases.
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19098096 P.E.Tomatis, S.M.Fabiane, F.Simona, P.Carloni, B.J.Sutton, and A.J.Vila (2008).
Adaptive protein evolution grants organismal fitness by improving catalysis and flexibility.
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PDB code: 3fcz
18230049 V.Gupta (2008).
Metallo beta lactamases in Pseudomonas aeruginosa and Acinetobacter species.
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18831550 Z.Hu, G.Periyannan, B.Bennett, and M.W.Crowder (2008).
Role of the Zn1 and Zn2 sites in metallo-beta-lactamase L1.
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18445468 Z.Hu, G.R.Periyannan, and M.W.Crowder (2008).
Folding strategy to prepare Co(II)-substituted metallo-beta-lactamase L1.
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Carbapenemases: the versatile beta-lactamases.
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Protonation state and substrate binding to B2 metallo-beta-lactamase CphA from Aeromonas hydrofila.
  Proteins, 69, 595-605.  
17403673 J.Morán-Barrio, J.M.González, M.N.Lisa, A.L.Costello, M.D.Peraro, P.Carloni, B.Bennett, D.L.Tierney, A.S.Limansky, A.M.Viale, and A.J.Vila (2007).
The metallo-beta-lactamase GOB is a mono-Zn(II) enzyme with a novel active site.
  J Biol Chem, 282, 18286-18293.  
17715135 L.I.Llarrull, M.F.Tioni, J.Kowalski, B.Bennett, and A.J.Vila (2007).
Evidence for a dinuclear active site in the metallo-beta-lactamase BcII with substoichiometric Co(II). A new model for metal uptake.
  J Biol Chem, 282, 30586-30595.  
17426028 L.I.Llarrull, S.M.Fabiane, J.M.Kowalski, B.Bennett, B.J.Sutton, and A.J.Vila (2007).
Asp-120 locates Zn2 for optimal metallo-beta-lactamase activity.
  J Biol Chem, 282, 18276-18285.
PDB code: 2uyx
17305336 M.Dal Peraro, A.J.Vila, P.Carloni, and M.L.Klein (2007).
Role of zinc content on the catalytic efficiency of B1 metallo beta-lactamases.
  J Am Chem Soc, 129, 2808-2816.  
16423823 D.Xu, D.Xie, and H.Guo (2006).
Catalytic mechanism of class B2 metallo-beta-lactamase.
  J Biol Chem, 281, 8740-8747.  
16684886 G.Hagelueken, T.M.Adams, L.Wiehlmann, U.Widow, H.Kolmar, B.Tümmler, D.W.Heinz, and W.D.Schubert (2006).
The crystal structure of SdsA1, an alkylsulfatase from Pseudomonas aeruginosa, defines a third class of sulfatases.
  Proc Natl Acad Sci U S A, 103, 7631-7636.
PDB codes: 2cfu 2cfz 2cg2 2cg3
16003817 B.Bauer-Siebenlist, S.Dechert, and F.Meyer (2005).
Biomimetic hydrolysis of penicillin G catalyzed by dinuclear zinc(II) complexes: structure-activity correlations in beta-lactamase model systems.
  Chemistry, 11, 5343-5352.  
15863831 C.Bebrone, C.Anne, K.De Vriendt, B.Devreese, G.M.Rossolini, J.Van Beeumen, J.M.Frère, and M.Galleni (2005).
Dramatic broadening of the substrate profile of the Aeromonas hydrophila CphA metallo-beta-lactamase by site-directed mutagenesis.
  J Biol Chem, 280, 28195-28202.  
15937993 J.Antony, J.P.Piquemal, and N.Gresh (2005).
Complexes of thiomandelate and captopril mercaptocarboxylate inhibitors to metallo-beta-lactamase by polarizable molecular mechanics. Validation on model binding sites by quantum chemistry.
  J Comput Chem, 26, 1131-1147.  
16172409 P.E.Tomatis, R.M.Rasia, L.Segovia, and A.J.Vila (2005).
Mimicking natural evolution in metallo-beta-lactamases through second-shell ligand mutations.
  Proc Natl Acad Sci U S A, 102, 13761-13766.  
16209700 T.R.Walsh (2005).
The emergence and implications of metallo-beta-lactamases in Gram-negative bacteria.
  Clin Microbiol Infect, 11, 2-9.  
15846405 Y.Tanaka, and K.Taira (2005).
Detection of RNA nucleobase metalation by NMR spectroscopy.
  Chem Commun (Camb), 0, 2069-2079.  
15215079 G.Garau, I.García-Sáez, C.Bebrone, C.Anne, P.Mercuri, M.Galleni, J.M.Frère, and O.Dideberg (2004).
Update of the standard numbering scheme for class B beta-lactamases.
  Antimicrob Agents Chemother, 48, 2347-2349.  
14747990 M.Dal Peraro, A.J.Vila, and P.Carloni (2004).
Substrate binding to mononuclear metallo-beta-lactamase from Bacillus cereus.
  Proteins, 54, 412-423.  
15159411 P.S.Mercuri, I.García-Sáez, K.De Vriendt, I.Thamm, B.Devreese, J.Van Beeumen, O.Dideberg, G.M.Rossolini, J.M.Frère, and M.Galleni (2004).
Probing the specificity of the subclass B3 FEZ-1 metallo-beta-lactamase by site-directed mutagenesis.
  J Biol Chem, 279, 33630-33638.  
15140877 R.M.Rasia, and A.J.Vila (2004).
Structural determinants of substrate binding to Bacillus cereus metallo-beta-lactamase.
  J Biol Chem, 279, 26046-26051.  
12724330 C.Damblon, M.Jensen, A.Ababou, I.Barsukov, C.Papamicael, C.J.Schofield, L.Olsen, R.Bauer, and G.C.Roberts (2003).
The inhibitor thiomandelic acid binds to both metal ions in metallo-beta-lactamase and induces positive cooperativity in metal binding.
  J Biol Chem, 278, 29240-29251.  
  12725860 C.Moali, C.Anne, J.Lamotte-Brasseur, S.Groslambert, B.Devreese, J.Van Beeumen, M.Galleni, and J.M.Frère (2003).
Analysis of the importance of the metallo-beta-lactamase active site loop in substrate binding and catalysis.
  Chem Biol, 10, 319-329.  
12574165 M.E.Meima, K.E.Weening, and P.Schaap (2003).
Characterization of a cAMP-stimulated cAMP phosphodiesterase in Dictyostelium discoideum.
  J Biol Chem, 278, 14356-14362.  
12824499 R.M.Rasia, M.Ceolín, and A.J.Vila (2003).
Grafting a new metal ligand in the cocatalytic site of B. cereus metallo-beta-lactamase: structural flexibility without loss of activity.
  Protein Sci, 12, 1538-1546.  
12454005 S.H.Liaw, S.J.Chen, T.P.Ko, C.S.Hsu, C.J.Chen, A.H.Wang, and Y.C.Tsai (2003).
Crystal structure of D-aminoacylase from Alcaligenes faecalis DA1. A novel subset of amidohydrolases and insights into the enzyme mechanism.
  J Biol Chem, 278, 4957-4962.
PDB code: 1m7j
12578382 S.Siemann, A.J.Clarke, T.Viswanatha, and G.I.Dmitrienko (2003).
Thiols as classical and slow-binding inhibitors of IMP-1 and other binuclear metallo-beta-lactamases.
  Biochemistry, 42, 1673-1683.  
11876827 A.L.Carenbauer, J.D.Garrity, G.Periyannan, R.B.Yates, and M.W.Crowder (2002).
Probing substrate binding to metallo-beta-lactamase L1 from Stenotrophomonas maltophilia by using site-directed mutagenesis.
  BMC Biochem, 3, 4.  
11940588 A.M.Simm, C.S.Higgins, A.L.Carenbauer, M.W.Crowder, J.H.Bateson, P.M.Bennett, A.R.Clarke, S.E.Halford, and T.R.Walsh (2002).
Characterization of monomeric L1 metallo-beta -lactamase and the role of the N-terminal extension in negative cooperativity and antibiotic hydrolysis.
  J Biol Chem, 277, 24744-24752.  
  11934488 B.J.Denny, P.A.Lambert, and P.W.West (2002).
The flavonoid galangin inhibits the L1 metallo-beta-lactamase from Stenotrophomonas maltophilia.
  FEMS Microbiol Lett, 208, 21-24.  
11847294 C.M.Gomes, C.Frazão, A.V.Xavier, J.Legall, and M.Teixeira (2002).
Functional control of the binuclear metal site in the metallo-beta-lactamase-like fold by subtle amino acid replacements.
  Protein Sci, 11, 707-712.  
12210153 J.Antony, N.Gresh, L.Olsen, L.Hemmingsen, C.J.Schofield, and R.Bauer (2002).
Binding of D- and L-captopril inhibitors to metallo-beta-lactamase studied by polarizable molecular mechanics and quantum mechanics.
  J Comput Chem, 23, 1281-1296.  
11714924 I.C.Materon, and T.Palzkill (2001).
Identification of residues critical for metallo-beta-lactamase function by codon randomization and selection.
  Protein Sci, 10, 2556-2565.  
11181339 M.Galleni, J.Lamotte-Brasseur, G.M.Rossolini, J.Spencer, O.Dideberg, and J.M.Frère (2001).
Standard numbering scheme for class B beta-lactamases.
  Antimicrob Agents Chemother, 45, 660-663.  
11257043 P.S.Mercuri, F.Bouillenne, L.Boschi, J.Lamotte-Brasseur, G.Amicosante, B.Devreese, J.van Beeumen, J.M.Frère, G.M.Rossolini, and M.Galleni (2001).
Biochemical characterization of the FEZ-1 metallo-beta-lactamase of Legionella gormanii ATCC 33297T produced in Escherichia coli.
  Antimicrob Agents Chemother, 45, 1254-1262.  
11327823 W.Fast, Z.Wang, and S.J.Benkovic (2001).
Familial mutations and zinc stoichiometry determine the rate-limiting step of nitrocefin hydrolysis by metallo-beta-lactamase from Bacteroides fragilis.
  Biochemistry, 40, 1640-1650.  
11060675 D.J.Payne, W.Du, and J.H.Bateson (2000).
beta-Lactamase epidemiology and the utility of established and novel beta-lactamase inhibitors.
  Expert Opin Investig Drugs, 9, 247-261.  
  10997907 K.D.Parris, L.Lin, A.Tam, R.Mathew, J.Hixon, M.Stahl, C.C.Fritz, J.Seehra, and W.S.Somers (2000).
Crystal structures of substrate binding to Bacillus subtilis holo-(acyl carrier protein) synthase reveal a novel trimeric arrangement of molecules resulting in three active sites.
  Structure, 8, 883-895.
PDB codes: 1f7l 1f7t 1f80
  10933508 L.Chantalat, E.Duée, M.Galleni, J.M.Frère, and O.Dideberg (2000).
Structural effects of the active site mutation cysteine to serine in Bacillus cereus zinc-beta-lactamase.
  Protein Sci, 9, 1402-1406.
PDB code: 1dxk
10757977 N.O.Concha, C.A.Janson, P.Rowling, S.Pearson, C.A.Cheever, B.P.Clarke, C.Lewis, M.Galleni, J.M.Frère, D.J.Payne, J.H.Bateson, and S.S.Abdel-Meguid (2000).
Crystal structure of the IMP-1 metallo beta-lactamase from Pseudomonas aeruginosa and its complex with a mercaptocarboxylate inhibitor: binding determinants of a potent, broad-spectrum inhibitor.
  Biochemistry, 39, 4288-4298.
PDB codes: 1dd6 1ddk
10736182 V.M.D'souza, B.Bennett, A.J.Copik, and R.C.Holz (2000).
Divalent metal binding properties of the methionyl aminopeptidase from Escherichia coli.
  Biochemistry, 39, 3817-3826.  
  10508780 A.D.Cameron, M.Ridderström, B.Olin, and B.Mannervik (1999).
Crystal structure of human glyoxalase II and its complex with a glutathione thiolester substrate analogue.
  Structure, 7, 1067-1078.
PDB codes: 1qh3 1qh5
  10508031 R.Nagano, Y.Adachi, H.Imamura, K.Yamada, T.Hashizume, and H.Morishima (1999).
Carbapenem derivatives as potential inhibitors of various beta-lactamases, including class B metallo-beta-lactamases.
  Antimicrob Agents Chemother, 43, 2497-2503.  
10545172 S.D.Scrofani, J.Chung, J.J.Huntley, S.J.Benkovic, P.E.Wright, and H.J.Dyson (1999).
NMR characterization of the metallo-beta-lactamase from Bacteroides fragilis and its interaction with a tight-binding inhibitor: role of an active-site loop.
  Biochemistry, 38, 14507-14514.  
10508665 Z.Wang, W.Fast, A.M.Valentine, and S.J.Benkovic (1999).
Metallo-beta-lactamase: structure and mechanism.
  Curr Opin Chem Biol, 3, 614-622.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.